Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS

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DESCRIPTION (provided by applicant): As of 2010, an estimated 34 million persons worldwide were living with human immunodeficiency virus (HIV) infection (Word Health Organization and UN estimations). Early after primary infection, HIV enters the CNS and causes cognitive and motor impairment in 30-60% of infected individuals, even in the antiretroviral era. As infected individuals are living longer, the prevalence of neurological complications due to HIV CNS infection has increased. The cellular basis and mechanisms by which HIV-1 causes neuropathogenesis, or NeuroAIDS, are still not well understood. Astrocytes are key cells in the CNS that regulate BBB integrity, CNS inflammation, immune responses and neuronal survival. HIV only infects a small percentage of these cells and minimal to undetectable viral production is detected. Nevertheless, our data demonstrate for first time that HIV infected astrocytes, through gap junction channels and perhaps hemichannels, can amplify inflammation and CNS damage. We hypothesize that Cx43 containing gap junctions (GJ) and hemichannels (uHC) amplify intercellular signals generated in few HIV infected astrocytes to surrounding uninfected cells resulting in cellular toxicity, BBB disruption and secretion of DKK1 leading to the CNS dysfunction often observed in the HIV infected population even in the current antiretroviral era, where viral replication is minimal. To address this hypothesis we will expand upon our extensive Preliminary Studies demonstrating the participation of these channels in astrocyte, neuronal and blood brain barrier (BBB) dysfunction, as well in amplification of cell activation and inflammation in HIV infected astrocytes and in uninfected cells. These data will characterize novel pathways of HIV toxicity within the brain and will identify the role of these channels in CNS dysfunction. The results obtained from this proposal should indicate potential novel therapeutic targets to limit the devastating consequences of NeuroAIDS. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page